Agents of earthy-musty taste and odor in water: evaluation of cytotoxicity, genotoxicity and toxicogenomics.

Considering the limited number of studies on the biological effects on human health of cyanobacterial compounds that cause taste and odor, the present study assessed the cytotoxic and genotoxic potentials of 2-methylisoborneol (2-MIB) and geosmin (GEO) using the MTT assay and the in vitro comet and cytokinesis-block micronucleus (CBMN-Cyt) assays in human HepG2 cells. The toxicogenomics of genes responsive to DNA damage and metabolization by the exposure of cells to 2-MIB and GEO were also investigated. The results showed that concentrations of 2-MIB and GEO above 100 and 75 µg/mL, respectively, were cytotoxic to HepG2 cells. Doses of 2-MIB (12.5, 25, 50, 75 and 100 µg/mL) and GEO (12.5, 25, 50, and 75 µg/mL) were unable to induce neither DNA damage nor events associated with chromosomal instability. Similarly, no concentration of each compound induced increments in the expression of CDKN1A, GADD45α, MDM2 and TP53 DNA damage responsive genes as well as in CYP1A1 and CYP1A2 metabolizing genes. Although cytotoxicity was observed, concentrations that caused it are much higher than those expected to occur in aquatic environments. Thus, environmentally relevant concentrations of both compounds are not expected to exhibit cytotoxicity or genotoxicity to humans.

In vivo and in vitro genotoxicity assessment of 2-methylisoborneol, causal agent of earthy-musty taste and odor in water.

The water eutrophication process by phosphorus and nitrogen allows cyanobacteria blooms which promote, among other effects, the generation and release of the metabolite 2-methylisoborneol (2-MIB) in the environment. This substance has been shown to be recalcitrant to conventional water treatment, degrading water quality. Considering the limited number of studies on the biological effects of 2-MIB in eukaryotic organisms, the present study assessed the genotoxicity of 2-MIB using the in vitro comet assay and cytokinesis block-micronucleus (CBMN-Cytome) assay on Chinese Hamster Ovary (CHO) cells and the in vivo Drosophila melanogaster Somatic Mutation and Recombination Test (SMART). The results showed that 2-MIB (125, 250 and 500 µg/mL) was unable to induce gene and chromosome mutations or events associated with mitotic recombination in the SMART. Similarly, four different concentrations (7.5, 15, 30 and 60 µg/mL) of 2-MIB did not induce increments in frequencies of micronuclei, nuclear buds, and nucleoplasmatic bridges in the CBMN-Cytome assay. In the comet assay, the positive results were restricted to the highest dose, 60 µg/mL of 2-MIB. The results obtained may help evaluate the genotoxic profile of extracellular algal products.

The antinociceptive effect of (-)-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice.

UNLABELLED: We used multiple pain models to investigate the effects of (-)-linalool, a monoterpene alcohol present in the essential oil of plants, on chronic inflammatory and neuropathic hypersensitivity in adult Swiss mice. Inflammatory or neuropathic hypersensitivity was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA) or partial sciatic nerve ligation (PSNL), respectively. Twenty-four hours after CFA injection, we used Von Frey filaments and acetone-evoked cooling to evaluate tactile and thermal hypersensitivity, respectively. A single i.p. injection of (-)-linalool (50 or 200 mg/kg) administered 30 minutes before testing reduced CFA-induced mechanical hypersensitivity. Similarly, (-)-linalool reduced acetone-evoked hypersensitivity up to 4 hours after treatment. Compared with vehicle, (-)-linalool produced a marked reduction in CFA-induced paw edema. (-)-Linalool also reduced mechanical hypersensitivity induced by PSNL 7 days after injury. Multiple (-)-linalool treatments given chronically (twice a day for 10 days; 50 mg/kg, i.p.) significantly reduced mechanical hypersensitivity induced by CFA and PSNL. This multidose strategy did not cause tolerance. We also reasoned that (-)-linalool might reduce nociceptive behavior in response to direct administration of inflammatory mediators. Therefore, we injected the cytokines IL-1ß (.1 pg/site) and TNF-α (1 pg/site) intrathecally. (-)-Linalool inhibited the biting response induced by IL-1ß and TNF-α. PERSPECTIVE: The article adds information about antinociceptive properties of (-)-linalool in chronic inflammatory and neuropathic hypersensitivity. It also indicates that (-)-linalool might be potentially interesting in the development of new clinically relevant drugs for the management of persistent pain.

Evidence for the involvement of ionotropic glutamatergic receptors on the antinociceptive effect of (-)-linalool in mice.

(-)-Linalool is a monoterpene alcohol which is present in the essential oils of several aromatic plants. Recent studies suggest that (-)-linalool has anti-inflammatory, antihyperalgesic and antinociceptive properties in different animal models. The present study investigated the contribution of glutamatergic system in the antinociception elicited by (-)-linalool in mice. Nociceptive response was characterized by the time that the animal spent licking the injected hind paw or biting the target organ following glutamate receptor agonist injections. (-)-Linalool administered by intraperitoneal (i.p., 10-200 mg/kg), oral (p.o., 5-100 mg/kg) or intrathecal (i.t., 0.1-3 microg/site) routes dose-dependently inhibited glutamate-induced nociception (20 micromol/paw, pH 7.4) with ID(50) values of 139.1 mg/kg; 34.6 mg/kg; and 0.9 microg/site, with inhibitions of 70+/-4; 72+/-7 and 74+/-8%, respectively. However, the intraplantar injection of (-)-linalool partially (49+/-9%) inhibited glutamate-induced nociception. Furthermore, (-)-linalool (200 mg/kg) given i.p. also reduced significantly the biting response caused by intrathecal injection of glutamate (30 microg/site), AMPA (25 ng/site), SP (135 ng/site), NMDA (25 ng/site) and kainate (23.5 ng/site), with inhibitions of 89+/-6%, 73+/-11%, 85+/-4%, 98+/-2% and 52+/-15%, respectively. However, (-)-linalool did not inhibit nociception induced by intrathecal injection of trans-ACPD (8.6 microg/site). Taken together, these results provide experimental evidences indicating that (-)-linalool produce marked antinociception against glutamate induced pain in mice, possible due mechanisms operated by ionotropic glutamate receptors, namely AMPA, NMDA and kainate.